Abstract
Modified vaccinia Ankara (MVA) is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetically adjuvanted MVA with the coding sequence of murine CD40L, a member of the tumor necrosis factor superfamily. Immunization of mice with this new vector led to strongly enhanced primary and memory CD8 T cell responses. Concordant with the enhanced CD8 T cell response, we could detect stronger activation of dendritic cells and higher systemic levels of innate cytokines (including IL-12p70) early after immunization. Interestingly, acquisition of memory characteristics (i.e., IL-7R expression) was accelerated after immunization with MVA-CD40L in comparison to non-adjuvanted MVA. Furthermore, the generated cytotoxic T-lymphocytes (CTLs) also showed improved functionality as demonstrated by intracellular cytokine staining and in vivo killing activity. Importantly, the superior CTL response after a single MVA-CD40L immunization was able to protect B cell deficient mice against a fatal infection with ectromelia virus. Taken together, we show that genetic adjuvantation of MVA can change strength, quality, and functionality of innate and adaptive immune responses. These data should facilitate a rational vaccine design with a focus on rapid induction of large numbers of CD8 T cells able to protect against specific diseases.
Highlights
Decades of successful vaccine development led to a drastic reduction in child mortality and debilitating illness resulting from infectious disease
Because of the Toll-like receptor (TLR)-stimulating properties of Modified vaccinia Ankara (MVA) [37, 38], we hypothesized that co-administration of MVA and a CD40 agonist might lead to enhanced CD8 T cell responses
We first set out to evaluate whether MVA-induced CD8 T cell responses can be amplified by an agonistic Ab to murine CD40
Summary
Decades of successful vaccine development led to a drastic reduction in child mortality and debilitating illness resulting from infectious disease Despite this impressive success, probably best exemplified by the eradication of smallpox, an estimated 5.6 million deaths annually can be accounted solely to the three most devastating diseases: malaria, tuberculosis, and HIV/AIDS [1]. Probably best exemplified by the eradication of smallpox, an estimated 5.6 million deaths annually can be accounted solely to the three most devastating diseases: malaria, tuberculosis, and HIV/AIDS [1] Other infectious diseases, such as Ebola and Marburg hemorrhagic fever, are quite rare but accompanied by high fatality rates. A safe live vector vaccine largely unaffected by pre-existing immunity [4,5,6] is modified vaccinia virus Ankara (MVA), originally created by Anton Mayr and further developed into a third-generation smallpox vaccine (MVA-BN®, IMVAMUNE®) [reviewed in [7]]
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